The present invention provides novel compounds that are useful as therapeutic agents, e.g., as antiviral agents, anticancer agents and metabolic moderators. The invention additionally relates to pharmaceutical compositions containing a compound of the invention as the active agent and to methods of using the novel compounds as therapeutic agents. The invention has application in the fields of biochemistry and medicinal chemistry and particularly provides nucleoside pyrophosphate and triphosphate analogs and related compounds for use in the treatment of disease.
Nucleotides are some of the most ubiquitous compounds in nature, one example of which is the adenosine triphosphate (xe2x80x9cATPxe2x80x9d) molecule shown below: 
The four principal ribonucleotide triphosphates may be polymerized to provide xe2x80x9cRNA,xe2x80x9d or xe2x80x9cribonucleic acid.xe2x80x9d In addition to its role in all normal cells, RNA represents the genetic material of one major class of pathogenic viruses known as the RNA viruses, examples of which are HIV and herpes viruses. When the sugar moiety is deoxyribose, the four principal deoxyribonucleotide triphosphates are polymerized into deoxyribonucleic acid strands, or xe2x80x9cDNA,xe2x80x9d the genetic material of all plants and animals. There is also another class of pathogenic viruses known as DNA viruses, examples of which include measles and mumps.
Much of the cell""s chemistry with regard to these various nucleotide compounds involves the addition, removal or transfer of one or more of the phosphates groups within the triphosphate moiety, as illustrated by the equilibrium transphosphorylation reaction wherein a phosphate group is transferred between uridine diphosphate (xe2x80x9cUDPxe2x80x9d) and ATP to give uridine triphosphate (xe2x80x9cUTPxe2x80x9d) and adenosine diphosphate (xe2x80x9cADPxe2x80x9d): 
The body triphosphorylates and dephosphorylates drug and metabolic intermediates at extremely high rates, resulting in a constant low level of triphosphorylated materials that are then used in cellular processes. Phosphates, pyrophosphates and triphosphates of antiviral drugs, nucleosides, inositol, isoprenoids, and other biochemical building blocks are critical intermediates in the biosynthesis of nucleosides, proteins and hormones.
In spite of the presence of phosphorylated compounds throughout the body, such compounds are elusive as pharmacological candidates due to the hydrolytic lability of the pyrophosphate and triphosphate groups and their short half-lives in the bloodstream. Thus, there is a need in the art for functionally equivalent compounds, i.e., compounds that are isosterically and electronically identical to the natural pyrophosphates and triphosphates, but that are hydrolytically and enzymatically more stable, and preferably have reduced toxicity as well.
The present invention is addressed to the aforementioned need in the art, and provides an unprecedented class of nucleoside-based therapeutic agents containing a functional group that is isosterically and electronically identical to a natural pyrophosphate or triphosphate group, wherein the agents are hydrolytically and enzymatically more stable than the xe2x80x9cnaturalxe2x80x9d pyrophosphate and triphosphate compounds. The therapeutic agents now provided are useful in a variety of contexts, e.g., as antiviral agents, anticancer agents, metabolic moderators, and the like. The novel compounds are also useful as starting materials or intermediates in the synthesis of other nucleoside-based therapeutic agents, as research tools for studying nucleoside triphosphates and pyrophosphates (the naturally occurring compounds hydrolyze readily, resulting in inconvenience in the laboratory), and in the sequential preparation of oligonucleotides and polynucleotides of interest.
In one aspect of the invention, novel compounds are provided having the structure of formula (I) 
wherein:
x and y are integers in the range of 1 to 3 inclusive;
R1 is a purine or pyrimidine base bound to a cyclic or acyclic sugar moiety, and may represent a single nucleoside or a nucleoside monomer contained within an oligonucleotide chain, wherein R1 is bound through either its 3xe2x80x2 or 5xe2x80x2 position;
R2 is selected from the group consisting of Nxe2x80x94Cxe2x88x92xe2x80x94ClO3, Nxe2x88x92xe2x80x94NO2 and Nxe2x88x92xe2x80x94SO2R3 wherein R3 is lower alkyl, halogenated lower alkyl, halo or amino;
X is
xe2x80x94X1xe2x80x94X2xe2x80x94 or xe2x80x94X3xe2x95x90Nxe2x80x94
X1 and Y are independently selected from the group consisting of 
wherein Z1 is selected from the group consisting of O, S, C(CN)2, NClO3, Nxe2x80x94NO2, Nxe2x80x94SO3 and Nxe2x80x94SO2R3, and Z2 is selected from the group consisting of Oxe2x88x92, Sxe2x88x92, lower alkyl, halogenated lower alkyl, halo, BH33, Nxe2x88x92xe2x80x94ClO3, Nxe2x88x92xe2x80x94NO2 and Nxe2x88x92xe2x80x94SO2R3, with the proviso that when R2 is Nxe2x88x92xe2x80x94ClO3, then Y is other than 
X2 is selected from the group consisting of O, S and Nxe2x80x94;
X3 is 
wherein Z3 and Z4 are independently selected from the group consisting of Oxe2x88x92Sxe2x88x92, lower alkyl, halogenated lower alkyl, halo, BH3xe2x88x92, Nxe2x88x92xe2x80x94ClO3, Nxe2x88x92xe2x80x94NO2 and Nxe2x88x92xe2x80x94SO2R3;
n is 0, 1 or 2, wherein when n is 2, the two X moieties may be the same or different; and
Cat is a cationic species.
In a related aspect of the invention, novel nucleoside based compounds are provided having the structure of formula (II) 
wherein R1, x, y and Cat are as defined above with respect to formula (I), the X moieties may be the same or different and are as defined above with respect to formula (I), q is an optional double bond, Y1 is Pxe2x95x90Z1, Asxe2x95x90Z1, Sxe2x95x90O or Sexe2x95x90O, and y2 is N, Nxe2x88x92, O or S, and further wherein (a) when Y1 is Sxe2x95x90O or Sexe2x95x90O, then q is a double bond and Y2 is N, and (b) when Y1 is Pxe2x95x90Z1 or Asxe2x95x90Z1, then q is absent and Y2 is Nxe2x88x92, O or S. Depending on the definition of each xe2x80x9cXxe2x80x9d moiety, structures of formula (II) may be represented by any of the following subgeneric formulae (IIa) through (IId) 
in which X1, X2, X3, Y1, Y2 and q are as defined previously, and wherein each structure bears a negative charge xe2x88x92x and is associated with x/y cationic moieties each bearing a positive charge +y.
In other aspects of the invention, novel compounds are provided that serve as starting materials or intermediates in the synthesis of compounds of formulae (I) and (II), and which are themselves useful as therapeutic agents. Such compounds have the structural formulae (III) and (IV) 
wherein X, Y, Y1, Y2, R2, Cat, n, x, y and q are as defined earlier, and LG is a leaving group displaceable by a nucleophile. For example, LG may be halo, displaceable by an alcohol ROH in the presence of base.
Other such compounds of the invention may be more generally represented by formulae (V) and (VI) 
which are identical to the compounds of formulae (III) and (IV) except that LG has been replaced with the substituent R4, which is a substituted or unsubstituted hydrocarbyl group of 1 to 24 carbon atoms, or, alternatively, a moiety defined as for R2, i.e., selected from the group consisting of Nxe2x88x92xe2x80x94ClO3, Nxe2x88x92xe2x80x94NO2 and Nxe2x88x92xe2x80x94SO2R3, with the proviso that when R4 is Nxe2x88x92xe2x80x94ClO3, Y1 is other than Sxe2x95x90O or Sexe2x95x90O.
The invention is also directed to pharmaceutical compositions containing a novel compound as provided herein, in combination with a pharmaceutically acceptable carrier. Preferably, such compositions are oral dosage forms and thus contain a carrier suitable for oral drug administration.
In addition, the invention provides methods of using a compound of the invention as a therapeutic agent. The compounds are useful as antiviral agents, anticancer agents, metabolic moderators, and the like, and can thus be administered to treat a variety of conditions, disorders and diseases. A primary use of the compounds, however, is in treating individuals suffering from a viral infection.
Definitions and Nomenclature:
It is to be understood that unless otherwise indicated, this invention is not limited to specific molecular structures, pharmaceutical compositions, methods of drug administration, or the like, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
It must be noted that, as used in the specification and the appended claims, the singular forms xe2x80x9ca,xe2x80x9d xe2x80x9canxe2x80x9d and xe2x80x9cthexe2x80x9d include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to xe2x80x9ca novel compoundxe2x80x9d in a pharmaceutical composition means that more than one of the novel compounds can be present in the composition, reference to xe2x80x9ca pharmaceutically acceptable carrierxe2x80x9d includes combinations of such carriers, and the like. Similarly, reference to xe2x80x9ca substituentxe2x80x9d as in a compound substituted with xe2x80x9ca substituentxe2x80x9d includes the possibility of substitution with more than one substituent, wherein the substituents may be the same or different.
In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings:
The term xe2x80x9calkylxe2x80x9d as used herein refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like. The term xe2x80x9clower alkylxe2x80x9d intends an alkyl group of one to six carbon atoms, preferably one to four carbon atoms. The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to a cyclic hydrocarbon of from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The term xe2x80x9calkoxyxe2x80x9d as used herein intends an alkyl group bound through a single, terminal ether linkage; that is, an xe2x80x9calkoxyxe2x80x9d group may be defined as xe2x80x94O-alkyl where alkyl is as defined above. A xe2x80x9clower alkoxyxe2x80x9d group intends an alkoxy group containing one to six, more preferably one to four, carbon atoms.
The term xe2x80x9carylxe2x80x9d as used herein, and unless otherwise specified, refers to an aromatic species containing 1 to 3 aromatic rings, either fused or linked, and either unsubstituted or substituted with 1 or more substituents typically selected from the group consisting of lower alkyl, lower alkoxy, halogen, and the like. Preferred aryl groups contain 1 aromatic ring or 2 fused or linked aromatic rings. The term xe2x80x9carylenexe2x80x9d refers to a difunctional aromatic species containing 1 to 3 aromatic rings substituted with 1 or more substituents as above. Preferred arylene substituents contain 1 aromatic ring (e.g., phenylene) or 2 fused or linked aromatic rings (e.g., biphenylylene).
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d is used in its conventional sense to refer to a chloro, bromo, fluoro or iodo substituent. The terms xe2x80x9chaloalkyl,xe2x80x9d xe2x80x9chaloalkenylxe2x80x9d or xe2x80x9chaloalkynylxe2x80x9d (or xe2x80x9chalogenated alkyl,xe2x80x9d xe2x80x9chalogenated alkenyl,xe2x80x9d or xe2x80x9chalogenated alkynylxe2x80x9d) refers to an alkyl, alkenyl or alkynyl group, respectively, in which at least one of the hydrogen atoms in the group has been replaced with a halogen atom.
The term xe2x80x9chydrocarbylxe2x80x9d is used in its conventional sense to refer to a hydrocarbon group containing carbon and hydrogen, and may be aliphatic, alicyclic or aromatic, or may contain a combination of aliphatic, alicyclic and/or aromatic moieties. Aliphatic and alicyclic hydrocarbyl may be saturated or they may contain one or more unsaturated bonds, typically double bonds. The hydrocarbyl moieties herein generally contain 1 to 24 carbon atoms, more typically 1 to 12 carbon atoms, and may be substituted with various substituents or contain nonhydrocarbyl linkages, e.g., xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Nxe2x88x92xe2x80x94, etc.
The term xe2x80x9csubstituentxe2x80x9d as used herein refers to a functional group or nonhydrogen substituent bound to an atom of a molecular moiety herein. Those skilled in the art will appreciate that the compounds and molecular segments drawn and defined herein may be unsubstituted, substituted as specifically indicated, or substituted with other substituents. Examples of substituents which may be present in the compounds of the invention include, but are not limited to, halo, particularly chloro and fluoro; hydroxy; alkoxy, particularly lower alkoxy, such as methoxy, n-propoxy and t-butoxy; primary amino (NH2); secondary amino, typically lower alkyl-substituted amino; tertiary amino, typically lower alkyl-disubstituted amino; nitro; acyloxy, which may be represented as Rxe2x80x2COOxe2x80x94; acylamido, which may be represented as Rxe2x80x2CONHxe2x80x94 and thiol analogs thereof (Rxe2x80x2CSOxe2x80x94 and Rxe2x80x2CSNHxe2x80x94, respectively), wherein Rxe2x80x2 is alkyl, typically lower alkyl; carboxy (xe2x80x94C(O)OH); alkoxycarbonyl (xe2x80x94C(O)ORxe2x80x2); carbamyl (xe2x80x94C(O)NH2); alkylcarbamyl (C(O)NHRxe2x80x2); alkylsulfonyl (Rxe2x80x2SO2xe2x80x94); and alkylphosphonyl (Rxe2x80x2P(ORxe2x80x2)Oxe2x80x94). For example, xe2x80x9csubstituted hydrocarbylxe2x80x9d refers to a xe2x80x9chydrocarbylxe2x80x9d group as defined above substituted with one or more, typically one to four, generally one or two, xe2x80x9csubstituentsxe2x80x9d as just defined, e.g., halo, alkoxy, amino, nitro or the like.
It will be appreciated that, as used herein, the term xe2x80x9cnucleosidexe2x80x9d will include those moieties which contain not only the known purine and pyrimidine bases, but also modified purine and pyrimidine bases and other heterocyclic bases which have been modified (these moieties are sometimes referred to herein, collectively, as xe2x80x9cpurine and pyrimidine bases and analogs thereofxe2x80x9d). Such modifications include methylated purines or pyrimidines, acylated purines or pyrimidines, and the like. Modified nucleosides will also include modifications on the sugar moiety, e.g., wherein one or more of the hydroxyl groups are replaced with halogen, aliphatic groups, or are functionalized as ethers, amines, or the like, as will be discussed in detail elsewhere herein. The term xe2x80x9cnucleosidexe2x80x9d is also intended to encompass nucleoside monomers as well as nucleosides present within an oligonucleotide chain, either at a terminus thereof or within the oligonucleotide backbone.
As used herein, the term xe2x80x9coligonucleotidexe2x80x9d shall be generic to polydeoxynucleotides (containing 2-deoxy-D-ribose), to polyribonucleotides (containing D-ribose), to any other type of polynucleotide which is an N-glycoside of a purine or pyrimidine base, and to other polymers containing nonnucleotidic backbones, providing that the polymers contain nucleobases in a configuration which allows for base pairing and base stacking, such as is found in DNA and RNA. The term xe2x80x9coligonucleotidexe2x80x9d includes double- and single-stranded DNA, as well as double- and single-stranded RNA and DNA:RNA hybrids, and also include known types of modifications, for example, labels which are known in the art, methylation, xe2x80x9ccaps,xe2x80x9d and the like.
By xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the selected active agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. Similarly, a xe2x80x9cpharmaceutically acceptablexe2x80x9d salt of a novel compound as provided herein is a salt or ester which is not biologically or otherwise undesirable. xe2x80x9cPharmaceutically or therapeutically effective dose or amountxe2x80x9d refers to a dosage level sufficient to induce a desired biological result. That result can be alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
The term xe2x80x9ctreatxe2x80x9d as in xe2x80x9cto treat a diseasexe2x80x9d is intended to include any means of treating a disease in a mammal, including (1) preventing the disease, i.e., avoiding any clinical symptoms of the disease, (2) inhibiting the disease, that is, arresting the development or progression of clinical symptoms, and/or (3) relieving the disease, i.e., causing regression of clinical symptoms.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not. For example, recitation of a double bond as xe2x80x9coptionally presentxe2x80x9d encompasses both the molecular moiety containing the double bond and the molecular moiety not containing the double bond.
In the molecular structures herein, single bonds are indicated in the conventional sense using a single line connecting two atoms, while double bonds are indicated in the conventional sense using a double line between two adjacent atoms. However, it will be appreciated that molecular structures can be drawn in different ways, and that in some cases a particular bond may be drawn as either a single or double bond, with both representations being chemically accurate and indicating the same structure.
The Novel Compounds:
In one embodiment, then, novel compounds are provided comprising nucleoside analogs having the general structure of formula (I) 
wherein the nucleoside is represented by R1 as will be discussed in further detail below, n is 0, 1 or 2, x and y are integers in the range of 1 to 3 inclusive, and R2, X, Y and Cat are defined as follows:
R2 is selected from the group consisting of Nxe2x88x92xe2x80x94ClO3, Nxe2x88x92xe2x80x94NO2 and Nxe2x88x92xe2x80x94SO2R3 wherein R3 is lower alkyl, halogenated lower alkyl, halo or amino, and a particularly preferred R2 group is Nxe2x88x92xe2x80x94ClO3.
X is
xe2x80x94X1xe2x80x94X2xe2x80x94or xe2x80x94X3xe2x95x90Nxe2x80x94
X1 and Y are independently selected from the group consisting of 
wherein Z1 is selected from the group consisting of O, S, C(CN)2, NClO3, Nxe2x80x94NO2, Nxe2x80x94SO3 and Nxe2x80x94SO2R3, and Z2 is selected from the group consisting of Oxe2x88x92, Sxe2x88x92, lower alkyl, halogenated lower alkyl, halo, BH3xe2x88x92, Nxe2x88x92xe2x80x94ClO3, Nxe2x88x92xe2x80x94NO2 and Nxe2x88x92xe2x80x94SO2R3, with the proviso that when R2 is Nxe2x88x92xe2x80x94ClO3, then Y is other than 
X2 is selected from the group consisting of O, S and Nxe2x88x92; and
X3 is 
wherein Z3 and Z4 are independently selected from the group consisting of Oxe2x88x92xe2x80x94, Sxe2x88x92, lower alkyl, halogenated lower alkyl, halo, BH3xe2x88x92, Nxe2x88x92xe2x80x94ClO3, Nxe2x88x92xe2x80x94NO2 and Nxe2x88x92xe2x80x94SO2R3.
Preferred X1 and Y moieties are 
wherein, in the former linkage, Z1 and Z2 are defined previously, with particularly preferred Z1 moieties selected from the group consisting of O, S, C(CN)2, NClO3, Nxe2x80x94SO3, Nxe2x80x94SO2CH3 and Nxe2x80x94SO2CF3, and particularly preferred Z2 moieties selected from the group consisting of Oxe2x88x92xe2x80x94, Sxe2x88x92, CH3, F, Cl, Nxe2x88x92xe2x80x94ClO3, Nxe2x88x92xe2x80x94SO2CH3 and Nxe2x88x92xe2x80x94SO2CF3.
The preferred X3 moiety is 
wherein Z3 and Z4 are as defined previously; particularly preferred Z3 and Z4 are halo or lower alkyl, e.g., chloro, fluoro, methyl, ethyl, and the like.
The moiety R1 is a nucleoside optionally contained within an oligonucleotide chain, and comprises a purine or a pyrimidine base or an analog thereof bound to a cyclic or acyclic sugar moiety. R1 is bound to the remainder of the molecule, i.e., the adjacent xe2x80x9cYxe2x80x9d moiety shown in structural formula (I), through either its 3xe2x80x2-hydroxyl group or its 5xe2x80x2-hydroxyl group. The purine or pyrimidine base may be conventional, e.g., adenine (A), thymine (T), cytosine (C), guanine (G) or uracil (U), or a protected form thereof, e.g., wherein the base is protected with a protecting group such as acyl, isobutyryl, benzoyl, or the like. The purine or pyrimidine base may also be an analog of the foregoing; suitable analogs will be known to those skilled in the art and are described in the pertinent texts and literature. Common analogs include, but are not limited to, 1-methyladenine, 2-methyladenine, N6-methyladenine, N6-isopentyladenine, 2-methylthio-N6-isopentyladenine, N,N-dimethyladenine, 8-bromoadenine, 2-thiocytosine, 3-methylcytosine, 5-methylcytosine, 5-ethylcytosine, 4-acetylcytosine, 1-methylguanine, 2-methylguanine, 7-methylguanine, 2,2-dimethylguanine, 8-bromoguanine, 8-chloroguanine, 8-aminoguanine, 8-methylguanine, 8-thioguanine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, 5-ethyluracil, 5-propyluracil, 5-methoxyuracil, 5-hydroxymethyluracil, 5-(carboxyhydroxymethyl)uracil, 5-(methylaminomethyl)uracil, 5-(carboxymethylaminomethyl)-uracil, 2-thiouracil, 5-methyl-2-thiouracil, 5-(2-bromovinyl)uracil, uracil-5-oxyacetic acid, uracil-5-oxyacetic acid methyl ester, pseudouracil, 1-methylpseudouracil, queosine, xcex2-D-galactosylqueosine, xcex2-D-mannosylqueosine, inosine, 1-methylinosine, hypoxanthine, xanthine, 2-aminopurine, 6-hydroxyaminopurine, 6-thiopurine and 2,6-diaminopurine. The sugar moiety conjugated to the purine or pyrimidine base may, is a monosaccharide which, as noted above, may be either cyclic or acyclic. Acyclic sugars typically contain 3-6 carbon atoms and include, for example, the acyclic sugar moieties present in acyclovir (xe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2xe2x80x94OH), ganciclovir (xe2x80x94CH2xe2x80x94Oxe2x80x94CH(CH2OH)xe2x80x94CH2xe2x80x94OH), and the like. Cyclic sugar moieties will generally be derived from furanose (a five-membered ring) or from pyranose (a six-membered ring), but more preferably from furanose forms. Examples of cyclic sugar moieties include threo-furanosyl (from threose, a four-carbon sugar), erythro-furanosyl (from erythrose, a four-carbon sugar), ribofuranosyl (from ribose, a five-carbon sugar), arabino-furanosyl (from arabinose, a five-carbon sugar), and xylo-furanosyl (from xylose, a five-carbon sugar). Other suitable cyclic sugar moieties include xe2x80x9cdeoxy,xe2x80x9d xe2x80x9cketo,xe2x80x9d and xe2x80x9cdehydroxe2x80x9d derivatives of the foregoing, and sugars substituted with amino groups, azide moieties, halogen substituents, aliphatic groups, and the like; examples of such modified sugar moieties are 2-ketopentofuranoses, 3-deoxyribose, 2,3-dideoxy-xcex2-glycero-pent-2-enofuranosyl (as in stavudine), 2,3-dideoxy-2-azido-pentofuranoyl (as in zidovudine, or xe2x80x9cAZTxe2x80x9d), and the like. Sugar moieties may be in any of their enantiomeric, diastereomeric or stereoisomeric forms, including, for example, D- or L-forms. It will be appreciated by those skilled in the art that numerous other sugar moieties may be employed in the context of the present invention.
The cationic moiety is typically a metal ion or an ammonium ion, either NH4+ or NR4+ wherein R is typically C1-C10 alkyl. Suitable metal ions include, for example, Na+, K+, Li+, Mg+2, Zn+2, Cs+, etc.
In preferred compounds, xe2x80x9cnxe2x80x9d is 0, so that the compound is a pyrophosphate analog rather than a triphosphate analog.
A preferred group of compounds encompassed by the general structure of formula (I) may be represented by formula (VII) 
wherein when n is 1, the compounds are of the formula (VIII), while when n is 0, the compounds are of the formula (IX) 
Within formula (VIII), particularly preferred compounds include, but are not limited to, structures of formulae (X) and (XI): 
In all of the above structures, R1, R2, X1, X2, Z1, Z2, x, y and Cat are as defined previously.
Representative compounds encompassed by formula (I) thus include, but are not limited to, the following: 
Other compounds of the invention that are nucleoside-based or incorporated in an oligonucleotide chain have the structural formula (II) 
wherein R1 is as defined above with respect to formula (I), the X moieties may be the same or different and are as defined above with respect to formula (I), q is an optional double bond, Y1 is Pxe2x95x90Z1, Asxe2x95x90Z1, Sxe2x95x90O or Sexe2x95x90O, and Y2 is N, Nxe2x88x92, O or S, and further wherein (a) when Y1 is Sxe2x95x90O or Sexe2x95x90O, then q is a double bond and Y2 is N, and (b) when Y1 is Pxe2x95x90Z1 or Asxe2x95x90Z1, then q is absent and Y2 is Nxe2x80x94, O or S. Generally, x and y are 1, 2 or 3, and Cat+y may be, for example, a metal ion (e.g., Na+, K+, Li30, Mg+2, Zn+2, Cs+, etc.) or an ammonium ion (e.g., NH4+ or NR4+ wherein R C1-C10 alkyl). Since each X is either
xe2x80x94X1xe2x80x94X2xe2x80x94 or xe2x80x94X3xe2x95x90Nxe2x80x94
formula (II) encompasses four distinct subgeneric structures of formulae (IIa), (IIb), (IIc) and (IId) 
in which X1, X2, X3, Y1, Y2 and q are as defined previously, and wherein the individual structures shown bear a negative charge -x and are associated with x/y cationic moieties Cat+y. Examples of such compounds include, but are not limited to, the following: 
In a further embodiment, xe2x80x9cfreexe2x80x9d anions not associated with a nucleoside are provided, which are useful to prepare compounds of structural formulae (I) and (II), and are themselves useful as therapeutic agents. One group of these compounds, shown in ionic association with a cationic moiety, has the structure of formula (III) 
Another group of these compounds has the structural formal (IV) 
Other preferred free anions of the invention may be more generally represented by formulae (V) and (VI) 
which are identical to the compounds of formulae (III) and (IV) except that LG has been replaced with the substituent R4, which is either substituted or unsubstituted C1-C24 hydrocarbyl or a moiety defined as for R2, i.e., selected from the group consisting of Nxe2x88x92xe2x80x94ClO3, Nxe2x88x92xe2x80x94NO2 and Nxe2x88x92xe2x80x94SO2R3, wherein when R4 is Nxe2x88x92xe2x80x94ClO3, then Y1 is other than Sxe2x95x90O or Sexe2x95x90O. If R4 is hydrocar any substituents may be present so long as the desired therapeutic activity is maintained and the resulting compounds are not in any way pharmacologically undesirable. Examples of substituents include, without limitation: halo, particularly chloro and fluoro; hydroxy; alkoxy, particularly lower alkoxy; amino; secondary amino, typically lower alkyl-substituted amino; tertiary amino, typically di(lower alkyl)-substituted amino; nitro; acyloxy, which may be represented as Rxe2x80x2COOxe2x80x94; acylamido, which may be represented as Rxe2x80x2CONHxe2x80x94 and thiol analogs thereof (Rxe2x80x2CSOxe2x80x94 and Rxe2x80x2CSNHxe2x80x94, respectively), wherein Rxe2x80x2 is alkyl, typically lower alkyl; carboxy (xe2x80x94C(O)OH); alkoxycarbonyl (xe2x80x94C(O)ORxe2x80x2); carbamyl (xe2x80x94C(O)NH2); alkylcarbamyl (C(O)NHRxe2x80x2); alkylsulfonyl (Rxe2x80x2SO2xe2x80x94); and alkylphosphonyl (xe2x80x2P(ORxe2x80x2)Oxe2x80x94) again, where Rxe2x80x2 is alkyl, typically lower alkyl, and may be substituted in a similar manner. R4 may also contain nonhydrocarbyl linkages, e.g., xe2x80x94Oxe2x80x94. xe2x80x94Sxe2x88x92, xe2x80x94Nxe2x95x90, xe2x80x94NRxe2x80x2xe2x80x94, and the like.
Representative compounds of structural formula (III), (IV), (V) and (VI) include, but are not limited to, the following: 
The compounds may be in the form of pharmaceutically acceptable salts or esters, or may be modified by appending one or more appropriate functionalities to enhance selected biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system, increase oral bioavailability, increase solubility to allow administration by injection, and the like.
Salts of the compounds can be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, (Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed. (New York: Wiley-Interscience, 1992). Acid addition salts are prepared from the free base (e.g., compounds having a neutral xe2x80x94NH2 or cyclic amine group) using conventional means, involving reaction with a suitable acid. Typically, the base form of the compound is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added at a temperature of about 0xc2x0 C. to about 100xc2x0 C., preferably at ambient temperature. The resulting salt either precipitates or may be brought out of solution by addition of a less polar solvent. Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. An acid addition salt may be reconverted to the free base by treatment with a suitable base.
Preferred acid addition salts of the present compounds are formed by association with an amine or polyamine that complexes with phosphate moieties or analogs thereof. The polyamine may be monomeric or polymeric, although preferred polyamines are the monomeric polyamines spermine, spermidine, putrescine, cadaverine and ethylenediamine, with spermine and spermidine particularly preferred.
Preparation of basic salts of acid moieties which may be present (e.g., carboxylic acid groups) are prepared in a similar manner using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, trimethylamine, or the like.
Preparation of esters involves functionalization of hydroxyl and/or carboxyl groups which may be present. These esters are typically acyl-substituted derivatives of free alcohol groups, i.e., moieties which are derived from carboxylic acids of the formula RCOOH where R is alkyl, and preferably is lower alkyl. Pharmaceutically acceptable esters may be prepared using methods known to those skilled in the art and/or described in the pertinent literature. Esters can be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures.
Certain of the novel compounds are chiral in nature and can thus be in enantiomerically pure form or in a racemic mixture. The invention is intended to encompass both the isomerically pure forms of the compounds shown and the racemic or diastereomeric mixtures thereof.
Utility:
The compounds of the invention can be administered to mammalian individuals, including humans, as therapeutic agents. For example, the compounds of the invention are useful as antiviral agents, anticancer agents, antiproliferative agents, antibiotics, metabolic moderators, and the like.
Use as antiviral agents: The present invention provides a method for the treatment of a patient afflicted with a viral infection comprising administering to the patient a therapeutically effective antiviral amount of a compound of the invention. The term xe2x80x9cviral infectionxe2x80x9d as used herein refers to an abnormal state or condition characterized by viral transformation of cells, viral replication and proliferation. Viral infections for which treatment with a compound of the invention will be particularly useful include: retroviruses such as, but not limited to, HTLV-I, HTLV-II, human immunodeficiency viruses, HTLV-III (AIDS virus), and the like; RNA viruses such as, but not limited to, influenza type A, B, and C, mumps, measles, rhinovirus, dengue, rubella, rabies, hepatitis virus A, encephalitis virus, and the like; DNA viruses such as, but not limited to, herpes viruses (including herpes simplex virus-1, herpes simplex virus-2, varicella-zoster virus, Epstein-Barr virus, human cytormegalovirus, human herpes virus 6, human herpes virus 7, and human herpes virus 8), vaccinia, papilloma virus, hepatitis virus B, and the like. A xe2x80x9ctherapeutically effective antiviral amountxe2x80x9d of a compound of the invention refers to an amount which is effective, upon single or multiple dose administration to the patient, in controlling the growth of the virus or in prolonging the survivability of the patient beyond that expected in the absence of such treatment. As used herein, xe2x80x9ccontrolling the growthxe2x80x9d of the virus refers to slowing, interrupting, arresting or stopping the viral transformation of cells or the replication and proliferation of the virus and does not necessarily indicate a total elimination of the virus.
Use as anticancer agents: The invention provides a method for using the compounds of the invention to treat cancer. In this embodiment, a patient afflicted with or susceptible to a neoplastic disease state is given a therapeutically effective antineoplastic amount of a compound of the invention. The term xe2x80x9cneoplastic disease statexe2x80x9d as used herein refers to an abnormal state or condition characterized by rapidly proliferating cell growth or neoplasm. Neoplastic disease states for which treatment with a compound of the invention will be particularly useful include: leukemias such as, but not limited to, acute lymphoblastic, chronic lymphocytic, acute myloblastic and chronic mylocytic leukemias; carcinomas, such as, but not limited to, those of the cervix, oesophagus, stomach, small intestines, colon and lungs; sarcomas, such as, but not limited to, oesteroma, osteosarcoma, lepoma, liposarcoma, hemangioma and hemangiosarcoma; melanomas, including amelanotic and melanotic; and mixed types of neoplasias such as, but not limited to, carcinosarcoma, lymphoid tissue type, follicular reticulum, cell sarcoma and Hodgkins Disease. A therapeutically effective antineoplastic amount of a compound of the invention refers to an amount which is effective, upon single or multiple dose administration to the patient, in preventing or controlling the growth of a neoplasm or in prolonging the survivability of the patient beyond that expected in the absence of such treatment. As used herein, xe2x80x9ccontrolling the growthxe2x80x9d of the neoplasm refers to slowing, interrupting, arresting or stopping its growth and metastases and does not necessarily indicate a total elimination of the neoplasm.
Use to treat infectious diseases: The compounds of the invention are also useful as antibiotic agents to treat individuals suffering from an infectious disease. Examples of infectious diseases that the compounds are useful to treat include, but are not limited to: systemic bacterial infections such as bartonellosis, brucellosis, Campylobacter infection, Bacillary angiomatosis, gonococcemia, Legionnaires"" disease, leptospirosis, listeriosis, lyme disease, melioidosis, meningococcemia, salmonellosis, syphilis, tularemia, typhoid fever, vibriosis and Yersinia infection; mycobacterial infections such as M. avium/M. intracellulare infections and tuberculosis; other bacterial infections such as actinomycosis, nocardiosis and Whipple""s disease; fungal infections such as aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis, paracoccidioidomycosis and sporotrichosis; parasitic infections such as amebiasis, babesiasis, Chagas"" disease, leishmaniasis, malaria, P. carinii infection, strongyloidiasis, toxocariasis, toxoplasmosis and trichinosis; mycoplasmal infections; chlamydial infections such as lymphogranuloma venereum, psittacosis and C. pneumoniae infection; localized pyogenic infections such as appendicitis, cholangitis, cholecystitis, diverticulitis, osteomyelitis, sinusitis and suppurative thrombophlebitis; and intravascular infections such as bacterial aortitis, bacterial endocarditis and vascular catheter infection.
Use as antiproliferative agents: The compounds of the invention are also useful to treat inflammatory disorders, immunologically mediated disorders and/or skin conditions typically associated with hyperproliferation of skin cells. Such disorders and conditions include, for example: rheumatoid arthritis (xe2x80x9cRAxe2x80x9d), degenerative joint disease (also known as xe2x80x9cDJDxe2x80x9d and xe2x80x9costeoarthritisxe2x80x9d); gout and pseudogout; juvenile rheumatoid arthritis (xe2x80x9cJRAxe2x80x9d), psoriasis; atopic dermatitis; contact dermatitis (also known as xe2x80x9callergic eczemaxe2x80x9d) and further eczematous dermatitises; exfoliative dermatitis; seborrhoeic dermatitis; dermatomyositis; polymyositis; scleroderma; vasculitis; Lichen planus; Pemphigus; bullous Pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitides; erythemas (including erythema multiforme and erythema nodosum); cutaneous eospinphilias; lupus erythematoses, including systemic lupus erythematosus and discoid lupus erythematosis; and Alopecia areata. 
Accordingly, the present invention includes pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the invention in association with a pharmaceutical carrier. The compounds of this invention can be administered by oral, parenteral (intramuscular, intraperitoneal, intravenous (I) or subcutaneous injection), topical, transdermal (either passively or using iontophoresis or electroporation), transmucosal (e.g., nasal, vaginal, rectal, or sublingual) or pulmonary (e.g., via dry powder inhalation) routes of administration or using bioerodible inserts and can be formulated in dosage forms appropriate for each route of administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch. Such dosage forms can also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating, agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, with the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately before use.
Compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax. Compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
Topical formulations will generally comprise ointments, creams, lotions, gels or solutions. Ointments will contain a conventional ointment base selected from the four recognized classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases. Lotions are preparations to be applied to the skin or mucosal surface without friction, and are typically liquid or semiliquid preparations in which solid particles, including the active agent, are present in a water or alcohol base. Lotions are usually suspensions of solids, and preferably, for the present purpose, comprise a liquid oily emulsion of the oil-in-water type. Creams, as known in the art, are viscous liquid or semisolid emulsions, either oil-in-water or water-in-oil. Topical formulations may also be in the form of a gel, i.e., a semisolid, suspension-type system, or in the form of a solution.
Finally, formulations of these drugs in dry powder form for delivery by a dry powder inhaler offer yet another means of administration. This overcomes many of the disadvantages of the oral and intravenous routes.
The dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient shall be such that a suitable dosage form is obtained. The selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment desired. Generally, dosage levels of between 0.001 to 10 mg/kg of body weight daily are administered to mammals.
The novel compounds are also useful as starting materials or intermediates in the synthesis of other nucleoside-based therapeutic agents, as research tools for studying nucleoside triphosphates and pyrophosphates (the naturally occurring compounds hydrolyze readily, resulting in inconvenience in the laboratory), and in the sequential preparation of oligonucleotides and polynucleotides of interest.